Dementia

1
Dementia

• Michael A Hill, MD
• Professor Of Psychiatry

2
Dementia An acquired syndrome characterized by

• Short-term memory impairment (i.e. learning) AND
• At least one of the following
• Aphasia - language memory impairments
• Apraxia - motor memory impairments
• Agnosia - sensory memory impairments
• Abstract thinking / Exec. function impairments
• Impairment in social and/or occupational fn
• Sxs not explainable by another disorder

3
Etiology Pathogenesis

• Dementia results from impaired functioning of
  multiple brain systems in both cortical and
  sub-cortical areas that are associated with
  short-term memory (i.e. learning) and other
  higher cognitive functions. Generally this is
  due to structural brain damage that is often
  progressive and relatively irreversible

4
Clinical Presentation of Dementia

• Always associated with cognitive disturbances and
  functional impairments
• Visuospatial impairments and behavioral
  disturbances are usually seen as well
• Specific symptoms will vary by type of dementia
  (Frontal lobe dementias present with personality
  change and executive dysfunction to a much
  greater degree than memory impairment)

5
Memory Impairments

• Difficulty learning or retaining new information
  (repeated conversations)
• Information retrieval deficits (cant recall
  names, list generation deficits)
• Personal episodic memory impairment (misplacing
  items)
• Declarative (semantic) memory (WHAT) gt procedural
  memory (HOW)

6
Language Deficits

• List-generation deficits verbal fluency (esp.
  in AD)
• Word-finding difficulties (naming problems)
• Less complex sentence structure
• Relatively preserved auditory comprehension (can
  understand directions)

7
Visuospatial impairments

• Visual recognition impairments (trouble
  recognizing familiar faces - CAPGRAS syndrome
  possible)
• Spatial deficits (getting lost in familiar
  surroundings, 3-D drawing deficits,
  constructional apraxia)

8
Functional Impairments

• Deficits appear first in IADLs (managing
  finances, driving, shopping, working, taking
  medications, keeping appointments)
• Eventually problems with ADLs (feeding, grooming,
  dressing, eating, toileting)
• Rate and specific pattern of loss will vary by
  individual and somewhat by diagnosis
• NB Functional impairment and performance on
  cognitive testing may not correlate strongly
  early in the course of dementia

9
Behavioral Symptoms

• Nearly universal and often the main focus of
  treatment. Inability to manage these symptoms is
  highly correlated with institutional placement.
• PERSONALITY CHANGE Occurs early
• passivity (apathy, social withdrawal)
• disinhibition (inappropriate sexual behavior or
  language, loss of social graces, aggression)
• self-centered behaviors (childishness, loss of
  generosity)

10
Epidemiology Prevalence increases with age
Lower numbers represent moderate to severe
dementia
11
Incidence Of Alzheimers Disease by Age
12
Diagnostic ApproachEarly Detection Screening

• Careful history from patient and reliable
  informant
• PE with focus on neurological exam and cognitive
  testing
• Cognitive testing tools such as MMSE are helpful.
  Score below 24-27 often concerning depending on
  premorbid abilities
• Functional Assessment tools such as the
  Functional Activities Questionnaire

13
Primary Care Screening Tools

• MMSE (normal varies somewhat by age and
  educational level an 80 y/o with only 4 years
  of education would be expected to only get a
  19/30)
• Clock Test easy to do, quick. Draw a clock,
  put numbers in correct locations, set hands to
  10 til 2.
• List generation number of animals that can be
  named in 60 seconds. lt12 is definitely abnormal,
  12-18 is marginal. Can also do words beginning
  with letter F. 10 in one minute is normal.
  Often very impaired in Alzheimers and some types
  of FTDs.
• Trails B testing is useful if frontal lobe
  deficits suspected (e.g. fronto-temporal
  dementias, AIDS dementia)
• Go No-Go Testing (inability to inhibit
  responses)

14
Cognitive Testing

• Serial 7s (5 answers) - If you can do it, thats
  good, but as many as 50 of normal elderly cant
  (WORLD backwards is not much better as only 62
  of elderly can do it with no errors)
• Orientation If you are disoriented thats bad,
  especially to month or year, however many early
  dementia patients are fully oriented (40)
• 3-item recall Not being able to recall 2/3 is
  bad as only 19 of dementia patients can do this,
  but 74 or normal elderly can
• MMSE Sensitivity 87, Specificity 82

15
MMSE norms by Age and Educational Level

• Educational level

16
Diagnostic Work-Up

• This is done to
• (1) rule out disorders besides dementia (e.g.
  delirium)
• (2) to identify reversible/treatable dementias
  (13)
• (3) to clarify the specific dementia syndrome
• Routine Assessment CBC with diff, serum
  electrolytes, Ca, glucose, BUN/CR, LFTs, TFTs,
  B12 folate, U/A, RPR, head imaging
• When indicated Sed. rate, HIV, CXR, heavy
  metals, LP, EEG, functional imaging, Lyme titers,
  endocrine studies, rheumatologic studies,
  Neuropsychological Testing

17
Guidelines For Use of Specialized Testing

• LP Suspicion of metastatic CA, CNS infections,
  neuropsyphilis, hydrocephalus, vasculitis. Also
  for dementia lt55 and rapidly progressive
  dementias
• Neuroimaging - consider in all new cases.
  However without focal symptoms or signs, seizures
  or gait disturbances in an individual over age 70
  - consider this optional
• Functional Imaging (SPECT, PET, MRS, fMRI) to
  clarify type of dementia when necessary (and in
  the future to track course of illness and
  response to tx)
• EEG - can help distinguish delirium from
  dementia, can help with seizure disorder and JCD
• Neuropsychological testing language barriers,
  MR, legal proceedings

18
Mild Cognitive Impairment

• Some cognitive deficits apparent on testing but
  not to dementia level (MMSE 24-29) range
• Minimal, if any, functional impairments
• 13-15 per year progress to dementia (A.D.) but
  not all progress and some improve (especially
  amnestic type aMCI)
• Predictors of progression ApoE4 alleles, poor
  performance on cued recall (amnestic type) and
  hippocampal atrophy by MRI

19
Pseudodementia

• More appropriately called reversible dementia
• The classic case is depressive pseudodementia
  with overstated cognitive impairments due to
  decreased concentration and poor effort
• However, depression may be a risk factor for
  dementia
• 50 of elderly patients with depressive
  pseduodementia have Alzheimers at 5 year
  follow-up

20
Late-Life Depression

• Defn First Major Depressive Episode occurs
  after age 65
• High correlation with dementia (50 go on to
  develop dementia within 3 years!)
• Many of these depression may be vascular or
  post-stroke depressions

21
Most Common Dementias

• Alzheimers Disease (AD) (50-75)
• Lewy Body Dementias (DLB) (10-30)
• Vascular Dementias (VaD) (15-20)
• Alcohol-related dementias (including Korsakoffs
  (infrequent) and etoh-induced))
• HIV dementia - most common dementia in those
  under age 55

22
Classification of Dementias

• Primary versus secondary based on the
  pathophysiology leading to damaged brain tissue
• Cortical versus sub-cortical depending on the
  cerebral location of the primary deficits
• Reversible versus irreversible depending on
  optimal treatment expectations
• Early (before age 65) versus late onset

23
ALZHEIMERS Pathophysiology

• Neuritic plaques -extracellular - abnormal
  insoluble amyloid (beta) protein fragments
• Neurofibrillary tangles - intracellular -
  disturbed tau-microtubule complexes
  (hyperphosphorylated tau)
• Cholinergic system degeneration with significant
  loss of neurons in certain areas (such as Nucleus
  Basalis of Meynert)
• Degeneration often begins in enterorhinal cortex
  and progresses to other limbic structures

24
(No Transcript)
25
Lewy Body Pathology

• Concentric spheres found within vacuoles
  (eosinophilic cytoplasmic inclusions)
• Seen in cortex, midbrain and brainstem neurons in
  patients with idiopathic parkinsonism,
  Alzheimer's disease and especially Lewy Body
  dementias
• The main structural component is
  alpha-synuclein. Ubiquitin is sometimes seen also.

26
(No Transcript)
27
Risk Factors for AD

• Age
• Family history / genetics
• Downs syndrome (trisomy 21)
• Head Trauma (esp. late in life) TBI may double
  risk
• Female gender (mixed results age bias and
  possible higher clinical expression in women)
• Ethnicity (Caucasians have the lowest risk)
• Late-onset depression (after age 65)
• Mild Cognitive Impairment (MCI)

28
Additional Risk Factors for Dementia

• Cerebrovascular disease (and the risk factors for
  CV disease including smoking, diabetes,
  hyperlipidemia, hypertension) is associated with
  vascular dementia risk
• Recurrent MDD may be associated with risk of
  dementia in general. (Kessing and Anderson found
  risk of dementia to be 6 times higher in patients
  with 5 or more prior episodes.)1
• Subclinical Hyperthyroidism (especially when
  antithyroid antibodies are present.2

1Kessing LF, Anderson PK. J Neurol Neurosurg
Psychiatry. 2004751662-1666 2Kalmijn S, Mehta
KM, Pols HA, et al. Clin Endocrinology (Oxf)
200053733-737
29
Genetic risk factors

• Chromosome 19 - autosomal recessive -
  Apolipoprotein E-4 allele - associated with
  late-onset disease (not relevant for
  non-caucasians)
• TOMM40 newly identified affects age of onset
• Chromosome 1, 14, 21 - autosomal dominant
  mutations - associated with early-onset/familial
  cases (5). Amyloid processing genes.
• CLU clusterin and PICALM (phosphatidylinositol-b
  inding clathin assembly protein)
• Chromosome 9 ubiquilin 1 polymorphisms
  needs replication
• BDNF val/val variant might be protective

30
Protective Factors in AD

• Education
• Anti-inflammatory agents (those that decrease
  amyloid production)
• Estrogen replacement therapy (/-)
• Smoking ()?nicotine/past use(-) CVD/current
  use
• APO E-3, CETP VV (longevity gene)
• Vitamin E other antioxidants?
• Homocysteine reduction
• Statin use (protects against PD, AD?)

31
Vascular dementia

• Includes Binswangers disease, MID, anoxic
  damage, post-CABG, inflammatory diseases
• RISK FACTORS age, hypertension, diabetes and
  hyperlipidemia
• 2nd most common dementia but incidence drops
  after the age of 75 (unlike Alzheimers disease)
• In one study, 87 of vascular dementias at
  autopsy had AD pathology1

1Nolan KA, Lino MM, et al. J Am Geriatr Soc,
199846597-604
32
Other less common dementias

• Primary degenerative dementias
• Diffuse Lewy Body dementias (7-26 of dementias)
• Frontotemporal dementias (Picks, ALS,
  Huntingtons)
• Neurological disorders associated with dementia
• PSP, Parkinsons dementia, NPH, neoplasms, head
  trauma, subdurals, demyelinating diseases

33
Less common dementias (cont.)

• Infectious causes
• neurosyphilis, Lyme disease
• post-encephalitic dementias (esp. herpes)
• viral, parasitic, bacterial and fungal
  meningitidies
• opportunistic infections or brain abscess
• Human prion disease (transmissible spongiform
  encephalopathies) - sCJD, Mad-cow
  disease(vCJD), Kuru, fatal familial insomnia

34
General medical causes of dementia

• Thyroid and adrenal diseases
• Vitamin deficiency states (thiamin, niacin, B12)
• Metabolic derangements (hepatic encephalopathy,
  dialysis dementia, etc.)
• Medications (sedatives, antihypertensives,
  narcotics, anticholinergics)
• Whipples Disease, sarcoidosis, Wilsons disease
• Toxins (heavy metals, organic poisons)

35
Rapidly Progressive Dementias

• Hashimotos Encephalitis (treatable with
  steroids)
• Cerebellar degeneration syndromes
• Transmissible spongiform encephalopathies (prion
  diseases)
• Paraneoplastic syndromes
• Postviral encephalitis
• Rare cases of AD, DLB, FTD

36
Economic Burden

• 80 to 100 billion per year in total treatment
  costs
• Alzheimers disease is the third most expensive
  disease to treat in the United States, following
  cancer and heart disease
• Currently 4 million people have Alzheimers
  disease in the U.S.
• More than 213,000 per family for the remainder
  of the patients life, including direct and
  indirect treatments costs (47,000 per patient
  per year)

37
General Treatment Principles

• Treatment Of Underlying Disease Process (Primary
  Treatment)
• Management Of Behaviors and Symptoms (Secondary
  Treatment)
• Caregiver Support and Education

38
Reversible Dementias

• May become irreversible if not treated soon
  enough
• Many dementias may be arrestible if not fully
  reversible
• Rule out depressive pseduodementia and delirium
  which can mimic dementia
• Some reversible dementias include hypoT4, B12
  def., some infections and tumors, drug-induced
  syndromes, etc.

39
Primary Treatment Strategies

• 1. Prevention
• Identify risks and mitigate
• Develop neuroprotective strategies for those at
  risk
• 2. Slow or halt progression of illness
• Understanding pathophysiology leads to treatment
  ideas
• 5 year delay in onset ---gt 1/3 decrease in
  prevalence
• Delaying institutionalization by 1 month saves
  1.2 billion/yr
• 3. Reverse symptoms
• Compensate through augmentation of remaining
  neurons or other systems
• Reversal of destructive processes regeneration
  of tissue

40
Delayed Onset Incidence
41
ALZHEIMERS Pathophysiology

• Neuritic plaques -extracellular - abnormal
  insoluble amyloid protein fragments
• Neurofibrillary tangles - intracellular -
  disturbed tau-microtubule complexes
  (hyperphosphorylated tau)
• Cholinergic system degeneration with significant
  loss of neurons in certain areas (such as Nucleus
  Basalis of Meynert)
• Degeneration often begins in enterorhinal cortex
  and progresses to other limbic structures

42
CHOLINERGIC SYSTEM STRATEGIES

• Reduce Serum anticholinergic load
• Precursor strategies (e.g. lecithin and choline)
• Receptor/synaptic strategies
• Metabolic strategies (anticholinesterases)

43
Serum Anticholinergic Load Cognitive Impairment

• 90 of community elderly sample had detectable SA
  levels
• An SA level gt2.8 pmol/Ml was 13X more likely to
  be associated with an MMSE of 24 or less in the
  general elderly population than in those with
  undetectable SA levels
• Univ Of Pittsburgh, AAGP 5th Annual Meeting, 2002

44
Commonly Prescribed Non-Psychiatric Drugs with
Significant Anticholinergic Activity

• cimetidine ranitidine
• prednisolone
• theophylline
• digoxin/Lanoxin
• furosemide
• nifedipine
• diphenhydramine (OTC)
• To a lesser extent codeine, warfarin,
  dipyradimole, isosorbide dinitrate

45
Current AChE Inhibitors
promotes binding of acetylcholine and stimulates
pre-synaptic release of ACh
46
(No Transcript)
47
(No Transcript)
48
Anticholinesterase Side Effects(i.e.
procholinergic)

• GI nausea, vomiting, diarrhea, increased
  gastric acid secretion
• Muscle cramps
• Fatigue
• Insomnia
• Syncope (2 vs 1 for placebo) (?bradycardia)

most common with rivastigmine
49
STRATEGIES TO SLOW OR HALT PROGESSION

• Calcium channel modulation and excitatotoxic
  systems attenuation (such as memantine)
• Anti-inflammatory/immunosuppressive
  strategies(e.g. NSAIDs)
• Gene therapy for defective protein regulation
• Toxin removal (Desferroxamine, clioquinol) /
  Ventriculoperitoneal shunting (COGNIShunt)
• Amyloid Protein strategies
• Other Neuroprotective strategies

50
Neuroprotective Strategies

• Nerve Growth Factor
• Acetyl-l(levo) carnitine (ALCAR)
• Estrogen
• Homocysteine reduction( folate, B6, B12)
• Antioxidants (Vit E, Gingko, deprenyl)
• Statins (Lipitor, Pravachol) (may lower
  abnormal amyloid levels)
• B-blockers in AD
• Rosiglitazone (Avandia) -anti-inflammatory,
  amyloid processing modulation activities
• Levetiracetam(Keppra) for aMCI reduces
  hippocampal hyperactivity

51
Nutraceutical Strategies

• Vitamin E (antioxidant)
• Homocysteine Reduction (folate, B6, B12)
• Beta-carotene
• Physicians Health Study II found a cognitive
  protective effect of 50 mg every other day over
  two decades of use
• Gingko (antioxidant)
• Resveratrol (a type of polyphenol found in red
  grape skins and thus red wine)
  ?anti-inflammatory, anti-aging, anti-cancer

52
Vitamin E

• Potent antioxidant properties
• Has been shown to slow progression at least as
  much as Deprenyl in one head-to-head study
• Recent study showed no difference from placebo in
  preventing progression from MCI to AD over 3 yrs
  but higher dietary intake over 10 years in
  non-demented patients resulted in 26 lower
  incidence of AD (Rotterdam Study)
• Few side effects even in high doses, though
  recent studies in Europe suggest a higher death
  rate in those on hi-dose Vitamin E
• Doses used in recent studies up to 1000 IU bid
• Consider 400-800 IU per day for prevention
• May work better if combined with Vitamin C

53
Days
54
Estrogen

• At this point the summary of many studies
  suggests that Hormone replacement therapy (HRT)
  is questionably effective in slowing the onset of
  AD in some women
• The earlier started, the better. Limited
  exposure may be best.
• Progesterone may be detrimental
• Tacrine response can be enhanced by Estrogen
• WHY? neurotrophic effects, incr. ChAT, high
  serum E2 suppresses Apo E

55
Statins

• Lovastatin(Mevacor), pravastatin(Pravachol),
  simvastatin(Zocor), atorvastatin(Lipitor)
• May prevent aggregation of B-amyloid in the
  brain by preventing cholesterol build up. May
  activate alpha-secretase.
• Conflicting evidence recent U of Wash study did
  not find a benefit, but looked at older
  individuals on statins only a short while.
• Earlier studies were more positive
• Not sure if all these drugs are equal Ability to
  enhance tissue plaminogen activator (tPA) and
  thus production of plasmin may be important.
  Plasmin may activate alpha-secretase and can also
  increase production of BDNF.
• AKA amyloid-beta peptide or ABeta

56
Memantine

• Glutamate
• is the principal excitatory neurotransmitter in
  brain regions associated with cognition and
  memory (i.e. it stimulates cholinergic neurons)
• Glutamate hypothesis of dementia
• suggests that overactivation of these neurons
  leads to excitatoxic damage to these brain areas
  (by allowing calcium to continuously leak in to
  cells). It is post-synaptic receptor sensitivity
  rather than excess release of glutamate that is
  the problem.
• Memantine
• is a weak antagonist of glutamate-gated NMDA
  receptor channels which prevents overactivation
  during memory formation but allows normal
  function

57
Memantine

• Trade name Namenda
• Dose range 5 to 20 mg (bid dosing)
• Side effects Constipation, somnolence,
  confusion/psychosis
• Agitation was significantly less likely in
  memantine groups than placebo

58
NSAID Use AD in Elderly Patients

• 2708 patients enrolled
• Examined NSAID use and prevalence of Alzheimers
  Disease
• NSAID users had 50 lower risk of being affected
  by AD
• Aspirin trended this way but was not significant
• Treatment studies have not shown any consistent
  benefits yet however.
• Landi, et al, Am J Geriatric Psychiatry,
  March-April, 2003

59
Abnormal Amyloid Protein Strategies

• Most genetic mutations associated with AD affect
  amyloid processing
• Senile plaques contain abnormal amyloid B
  fragments (that precipitate out of solution
  easily)
• Attack enzymatic pathways that lead to production
  of abnormal type and amount of amyloid ( beta or
  gamma-secretase inhibitors)
• Enhance alpha-secretase system to promote normal
  amyloid
• Prevent aggregation (NSAIDS may do this!)
• Alter the abnormal gene expression
• GAG mimetics (glycosaminoglycans) Alzhemed
  interferes with formation of insoluble amyloid
  protein fragments

60
Anti-amyloid Treatments

• Gamma and beta secreatase inhibitors
• Poor response to gamma inhibitors in Phase III
  trials so far
• Aggregation inhibitors (e.g. tamiprosate)
  negative in Phase III trials
• Immunotherapy
• AN-1792 worked in mice but high rate of
  encephalitis in humans less powerful antigen
  form being developed
• Passive immunization bapineuzumab monocloncal
  AB against amyloid-B protein
• Autophagy enhancers

61
Reversal Strategies

• Destroy the current plaques/amyloid
• Vaccination Strategy AN-1792 vaccine is in
  testing. This is an amyloid B protein fragment
  which can induce antibodies that bind to plaques
  and activate microglial destruction processes.
  Trial halted b/o menigoencephalopathies
• Plaque busters
• Alzhemed prevents Amyloid B fragments from
  forming fibrils
• Clioquinol - A metal-protein-attenuating compound
  (MPAC) that inhibits zinc and copper ions from
  binding to beta-amyloid, thereby helping to
  dissolve it and prevent it from accumulating.
• Transthyretin shows promise at interfering with
  toxic effects
• Generate new tissue -
• Neuroregeneration strategies (STEM cells)
• Neurotransplantation strategies

62
Other Drugs in the Pipeline

• Tau protein modulators (to prevent abnormal
  phosphorylated tau protein
• Beta and gamma-secretase inhibitors
• Alpha secretase stimulators
• Bryostatin CA drug that stimulates brain
  protein production. Reduces B-amyloid levels in
  mice, enhances memory and learning.
• New generation NSAIDS (flubiprofen) testing in
  humans looks promising
• Immune enhancers (immunoglobulin)
• New vaccines and new anticholinesterases
  (huperzine)

63
Caregiver Burden

• Alzheimers caregivers spend an average of 69 to
  100 hours per week providing care
• Caregivers of patients suffering from
  dementia(compared to control subjects) reported
• 46 more physician visits
• Over 70 more prescribed drugs
• More likely to be hospitalized
• More than 50 of caregivers are at risk for
  clinical depression

64
Staging of Dementias

• MILD difficulties with checkbook maintenance,
  complex meal preparations, complicated medication
  schedules
• MODERATE difficulties with simple food
  preparation, household or yard work. May need
  some assistance with self-care
• SEVERE Need considerable assistance with
  feeding, grooming and toileting
• PROFOUND Largely oblivious to surroundings,
  totally dependent
• TERMINAL Bed bound require constant care

65
Common Associated Problems

• depression (occurs in 20-40 - esp. AD and VaD)
• psychosis (occurs in 30- 50) - usually see
  paranoid delusions (theft, infidelity)
• wandering/purposeless activity
• agitation/threatening behavior
• sleep disturbances
• delirium - minor insults can lead to major
  decompensations

66
DELIRIUM

• Definition - transient, usually reversible,
  dysfunction of global cerebral metabolism or
  physiology that has an acute or subacute onset
  manifested by a wide array of neuropsychiatric
  abnormalities, and often associated with
  life-threatening medical disorders
• AKA acute organic brain syndrome, acute
  encephalopathy

67
Delirium (signs and sx)

• Symptoms Impairments of alertness (arousal) and
  attention are the core deficits. Symptoms will
  wax and wane as alertness and attention decreases
  and increases. Functions that depend on
  attention and alertness including orientation,
  perception, working memory and awareness will be
  impaired leading to a host of potential secondary
  sx such as psychosis, sleep-wake cycle
  disturbances, agitation, anxiety, and
  neurological abnormalities (dysgraphia,
  constructional apraxia, tremor, etc.)
• Signs EEG slowing, asterixis, sleep/wake cycle
  changes, S100B elevations in CSF?
• (S100B is a 21-kDa calcium-binding protein
  produced and released primarily by astrocytes in
  the CNS, where it exerts neurotropic and
  gliotropic actions. Several studies have
  investigated the potential role of S100B as a
  peripheral biochemical marker of neural injury.

68
Delirium vs Dementia(summary)

• General rules of thumb
• Delirium Dementia
• acute chronic
• reversible
  irreversible
• physiological structural
• primary attention primary memory
• deficits
  deficits
• Delirium and dementia can coexist in fact
  delirium is very common in demented patients

69
DSM-IV DIAGNOSIS

• Criteria
• A. Disturbance of consciousness with decreased
  attention/focus
• B. Change in cognition or development of
  perceptual disturbances
• C. Develops rapidly and fluctuates over time
• Code as Delirium due to...
• 1. General Medical Condition (specify)
• 2. Substance Intoxication/Withdrawal
• 3. Multiple Etiologies
• 4. NOS

70
Epidemiology of Delirium

• Very Common - 10-15 med/surg inpatients (30 if
  elderly) 2/3 of patients admitted from NH have
  delirium
• 30 of Adult Burn Patients
• 80 of delirious patients have pre-existing
  dementia
• Mortality rates for elderly hospitalized patients
  with delirium is as high as 65 in some studies
  (double the non-delirious rate)
• As many as two thirds of deliria go undetected
• Annual costs exceed 8 billion
• All sudden mental status changes in dementia
  patients should be considered a delirium until
  proven otherwise

71
Etiology of delirium

• many potential causes
• often multifactorial (only 56 have a single
  probable etiology)
• infections, metabolic derangements, anoxia, drug
  intoxications, withdrawals, CNS disease, toxins,
  fevers, etc.
• susceptibility increased by aging, brain injury
  (esp. dementia and CV disease), polypharmacy
  (esp. anticholinergic load), malnutrition and
  fever
• suspect UTI, dehydration and/or pneumonia in
  dementia patients with delirium

72
DELIRIUM - General Treatment

• Treatment
• Must look for medical cause(s) and treat as the
  primary intervention
• Secondary symptoms can be helped by drugs such as
  haloperidol or risperidone (unless the cause of
  the delirium is NMS) and by reorientation
  strategies. Quetiapine has also become popular
  due to minimal dopamine blocking properties
• Avoid anticholinergic, antihistaminic, and
  sedating drugs

73
Specific Treatments

• Anticholinesterases may be useful if cholinergic
  systems are impaired (which may be the case in
  most deliria)
• Thiamine for W-K, benzodiazepines for
  etoh/sedative withdrawal delirium
• Benzodiazepine antagonists have been useful in
  some cases of hepatic encephalopathy
• What about stimulants?

74
Behavioral Problems in AD

• Almost universally a problem at some point
• 60 of AD at any one time exhibiting significant
  symptoms (usually delusions and/or agitation)
• Common problems by order of prevalence
• agitation
• depression
• delusions/psychosis
• Additional behavioral problems
• disinhibition, apathy, personality change,
  anxiety, wandering, insomnia

75
Causes of Behavioral Problems

• Biological (due to the disease process itself
  e.g.)
• Psychological (loss of function and autonomy,
  attempts to maintain some control, denial of
  deficits, etc.)
• Social (family distress, economic issues, family
  conflicts over care)
• Environmental (increased sensitivity to changes,
  issues of safety, etc.)

76
General Treatment Strategies

• Define symptoms clearly
• Rule out other psychiatric illness (e.g. MDD)
• Rule out medical causes for the symptoms (e.g.
  intercurrent illness, medication reactions, etc.)
• Identify non-pharmacologic strategies
• Pharmacotherapy

77
Environmental Strategies

• Identify provocations and rectify if possible
• Appropriate re-orientation strategies task
  simplification
• Optimize sensory input i.e. correct visual and
  hearing impairments
• Behavior management strategies that respect the
  patients need for control and autonomy
  (announcing intentions, single-step instructions
  e.g.)
• Optimize physical activity, social stimulation,
  reminiscing

78
Management Issues

• Alleviate patients distress
• Reduce care-giver burden
• Delay institutionalization
• Assure safety
• Patients often become more like themselves

79
Caregiver information and support

• Caregivers should
• Encourage independence for the Alzheimers
  patient without sacrificing security
• Assist the patient, but only if necessary (i.e.
  allow the patient as much control as possible)
• Learn to compromise
• Develop ways to share activities
• Establish a support network get other family
  involved
• Educate themselves (alzheimers.org)

80
Depression and Alzheimers

• Common early in the course of the illness
• Incidence 40-50
• Use SSRIs first avoid anticholinergic
  antidepressants
• ECT can be helpful but may temporarily worsen
  cognitive symptoms

81
Treatment of Depression

• Recognize that irritability and/or apathy
  /withdrawal may be indicative of depression
• Allow patient choices and control
• Identify pleasurable activities (such as singing
  old songs, pet therapy, etc.)
• Cognitive enhancers (e.g. Aricept) may help
• Consider Ritalin for apathy, poor appetite

82
Agitation

• Non-aggressive
• verbal complaining, constant requests for
  attention, repetition of words, constant talk,
  screaming
• physical pacing, disrobing, stereotypies, trying
  to get to a different place
• Aggressive
• Verbal threats, name calling, obscenities
• Non-verbal biting, scratching, spitting,
  kicking, pushing, swinging fists

83
Treatment of Agitation/Violence

• Identify and reduce provocative stimuli if
  possible
• Optimize communication with patient
• Environmental modifications
• Pharmacotherapy - target underlying cause
  (neuroleptics, antidepressants, mood stabilizers,
  beta blockers, buspirone, trazodone)

84
Medications for Agitation

• Buspirone Takes a while to work
• Antidepressants (SSRIs, Trazodone)
• Anticonvulsants (esp. valproate)
• Atypical Antipsychotics (stroke/mortality risk
  concerning)
• Low dose narcotics? Marinol?
• Anticholinesterases and/or memantine
• Estrogen?
• Benzos ataxia, worsening memory and
  disinhibition are problematic.

85
Treatment of Psychosis

• Recognize common delusions as relating to
  impaired STM (improving memory may help - e.g.
  donepezil)
• Delusions often fade with time even without tx
• Traditional antipsychotics
• Low potency (chlorpromazine) orthostasis,
  sedation, anticholinergic
• High potency (haloperidol) EPS/TD but otherwise
  well tolerated
• New generations drugs (e.g. olanzapine,
  quetiapine, risperidone)- less EPS/TD but still
  see anticholinergic, BP and sedative effects

86
Atypical Antipsychotics Risk of Serious Adverse
Events

• Retrospective review revealed a small (2-3) but
  2 fold increase in risk of stroke in demented
  patients receiving these agents compared to
  placebo.12
• FDA required Black Box warning due to 1.6 to
  1.7-fold increase in mortality in pooled sample
  of gt5000 persons with dementia exposed to these
  agents (in particular this was found in studies
  of olanzapine, risperidone and aripiprazole)

12Hermann N, et al. CNS Drugs 200519(2)91-103
87
Atypical Antipsychotics Risk of Serious Adverse
Events

• The risk with traditional antipsychotics may be
  even higher.13
• Recent meta-analysis of 15 trials (some
  unpublished) by Schneider in JAMA14 confirmed a
  small increase in death with these agents
  compared with placebo. This was significant for
  the pooled data but not the individual drug data.
  The OR was 1.54

13Gill S, et al. BMJ 2005330(7489)445
14Schneider LS, et al. JAMA 2005294(15)1934-1943
88
Recommendations on Use of Antipsychotic Agents in
Dementia

• Have a justifiable use -gt severe, distressing
  psychotic symptoms e.g. Do not use first-line
  for non-psychotic behavioral disturbances.
• Use lowest amounts for shortest possible times
• Caution patients and family about risk but
  remember that older agents may be worse, and
  there is little data on other psychotropics to
  suggest that they are safe.

89
Treatment of Wandering

• Lock doors (but in a way that is confusing for AD
  patient but not others)
• Wander guards
• Decrease agitation (see above)
• Environmental changes (such as using visual
  patterns to redirect wandering, wander gardens)

90
Apathy

• Common symptom of frontal lobe damage which can
  occur in most dementias
• Can be part of depression but usually a
  stand-alone symptom
• Bothers family more than patient, so hard to
  treat
• Donepezil has been shown in one study to delay
  onset of this sx
• Stimulants may or may not help

Int J Psychiatry. 2011 26(2)
91
Treatment of Insomnia

• Sleep hygiene (avoid caffeine, etc.)
• Treat causative psychiatric or medical disorders
• Phsysiological remedies - melatonin, warm milk,
  lavendar oil
• Medications - Benadryl, benzos, sedating
  antidepressants or antipsychotics (all these
  drugs can make memory and confusion worse)
• Light Therapy - to reset natural circadian
  rhythms for sleep

92
Sexually Disinhibited Behavior

• Includes sexual talk, sexual acts, implied sex
  acts, false reporting
• Treatment or sexual aggression and/or
  disinhibition
• Psychosocial reminders, move to private room,
  clothing modification, staff education
• Pharmacological SSRIs, antiandrogens
  (medroxyprogesterone acetate, cyproterone
  acetate), estrogen patches

93
Wandering Behavior

• 4-26 of dementia patients in Nursing Homes
  wander
• If not located within 24 hours, 46 will die
  (usually of hypothermia or dehydration)
• TX Vigilance, wander guards, complicated exits,
  reduce agitation
• Safe Return nationwide identification program
  alert system for law enforcement officials, TV
  stations